IL-17-driven mechanisms for tumor progression and resistance to therapies

IL-17 驱动的肿瘤进展和治疗耐药机制

• 批准号: 10493940
• 负责人: Xiaoxia Li
• 金额: $ 52.03万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-13 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10493940
• 关键词: Animal Model; Automobile Driving; Award; Binding; CD8-Positive T-Lymphocytes; Cells; Chemoresistance; Chronic; Cisplatin; Collagen; Cutaneous; Data; Deposition; Development; Dissection; Environment; Epidermal Growth Factor Receptor; Exclusion; Fibroblasts; Genes; Genetic; Goals; Head and Neck Squamous Cell Carcinoma; Human; Immune; Immune checkpoint inhibitor; Immunotherapy; Infiltration; Inflammation; Inflammatory; Interleukin-17; Interleukins; Knowledge; Link; MAPK7 gene; Malignant Neoplasms; Mediating; Messenger RNA; Molecular; Mus; Myeloid-derived suppressor cells; Pathogenicity; Population; Process; Prognosis; Proteins; RNA Binding; Refractory; Reporting; Resistance; Role; Shapes; Signal Transduction; Solid Neoplasm; Squamous cell carcinoma; Standardization; Statistical Data Interpretation; Stromal Cells; Testing; Therapeutic; Transcript; Transforming Growth Factor beta; Translations; Work; antagonist; anti-PD-1; anti-PD1 therapy; base; cancer cell; cancer cell differentiation; cancer therapy; chemotherapy; cytokine; design; improved; in vivo; insight; neoplastic cell; novel therapeutic intervention; pre-clinical assessment; prevent; programs; response; single cell analysis; stem; stem cells; stemness; therapeutic target; therapy resistant; tool; transcriptome; transcriptomics; treatment response; tumor; tumor microenvironment; tumor progression; tumorigenesis; wound healing

Project Summary While the relationship between chronic inflammation and cancer is well recognized, knowledge of the cellular and molecular mechanisms that link these processes continues to evolve. Intratumoral interleukin 17A (IL-17) levels are associated with poor prognosis for a variety of solid tumors in human. The overall goal of this application is to investigate the mechanisms of IL-17-mediated cancer progression, focusing on tumor responses to anti-cancer therapies. Our recent preliminary data revealed that IL-17 engages both cancer cells and tumor microenvironment to synergistically promote cancer progression. Firstly, work supported by this award identified a non-canonical IL-17-induced EGFR-mediated ERK5 signaling cascade critical for tumorigenesis. Our new preliminary study revealed an Lrig1+ stem-like tumor cell population in squamous cell carcinoma that are highly responsive to IL-17 with EGFR-ERK5 activation. Transcriptomic profiling revealed a link between IL-17-ERK5 axis in human and mouse Lrig1+ stem-like tumor cells with NRF2-mediated antioxidation and Wnt5a-dependent induction of stemness. Lineage tracing showed that IL-17 rendered these Lrig1+ stem-like tumor cells resistance to chemotherapy, which were also enriched by anti-PD1 treatment. Secondly, we found that canonical IL-17 signaling operates in both tumor cells and stromal cells to dictate a tumor-promoting and immune suppressive environment. In tumor cells, IL-17 synergizes with other inflammatory cytokines to orchestrate an intratumoral cancer promoting inflammation via the induction of specific effector molecules. In cancer-associated fibroblasts, IL-17 signaling helps to establish an immune exclusion zone to prevent the infiltration of CD8+ T cells. Deletion of IL-17R in CAFs rendered these tumors sensitive to immune therapy. Based on these observations, we hypothesize that canonical and non-canonical IL-17 signaling in cancer cells and CAFs coordinately drive cancer progression and resistance to therapies. To test this hypothesis, we will (1) Investigate how IL-17R-EGFR axis in Lrig1+ stem-like tumor cells renders resistance to anti-cancer therapies; (2) Elucidate the mechanism by which IL-17 shapes the pro-tumor immune exclusive tumor microenvironment. Program Interactions: This Project will be critically informed by and also provide necessary information to the other Projects in the Program at multiple levels. Project 1 and Project 2 will investigate the antagonistic interplay between IFNβ and TGFβ in cancer cell differentiation. Informed by those studies, we will determine whether STING-induced IFNβ can be used to eradicate Lrig1+ cells to improve responses to anti-cancer therapies. We will take advantage of the Animal Model, Immunotyping and Analytics Core B to standardize our in vivo analyses, including preclinical assessment of cancer therapeutics and characterization of the tumor microenvironment (TME). Statistical analyses will be performed by Program Biostatistician Dr. Bo Hu and Program Bioinformatician Dr. Fulai Jin (Core B).

项目摘要 虽然慢性炎症与癌症之间的关系已得到充分认识，但对细胞的了解 以及连接这些过程的分子机制继续发展。肿瘤内白介素17a（IL-17） 水平与人类各种实体瘤的预后不良有关。总体目标 应用是研究IL-17介导的癌症进展的机制，重点是肿瘤反应 进行抗癌疗法。我们最近的初步数据表明，IL-17与癌细胞和肿瘤均参与 微环境协同促进癌症的进展。首先，确定该奖项支持的工作 非传统IL-17诱导的EGFR介导的ERK5信号传导级联对于肿瘤发生至关重要。我们的新 初步研究表明，在鳞状细胞癌中有LRIG1+茎样细胞群 用EGFR-ERK5激活对IL-17响应。转录组分析揭示了IL-17-ERK5之间的联系 NRF2介导的抗氧化和Wnt5a依赖性的人和小鼠LRIG1+茎状肿瘤细胞中的轴 诱导干性。谱系跟踪表明，IL-17呈现了这些LRIG1+茎状肿瘤细胞的抗性 化学疗法也通过抗PD1治疗富集。其次，我们发现规范IL-17 肿瘤细胞和基质细胞中的信号操作决定肿瘤促进和免疫抑制 环境。在肿瘤细胞中，IL-17与其他炎症细胞因子协同策划肿瘤内 通过诱导特定效应子分子促进炎症的癌症。在与癌症相关的成纤维细胞中 IL-17信号传导有助于建立一个免疫排除区，以防止CD8+ T细胞的渗透。删除 CAF中IL-17R的摄入使这些肿瘤对免疫治疗敏感。基于这些观察，我们 假设癌细胞和CAF中的规范和非典型IL-17信号传导协同驱动癌症 进展和抗药性。为了检验这一假设，我们将（1）研究IL-17R-EGFR轴如何 在LRIG1+ Stem样肿瘤细胞中，对抗癌疗法具有抗性； （2）阐明该机制 IL-17塑造了亲肿瘤免疫肿瘤微环境。程序互动：这个项目将 要批判性地告知并向计划中的其他项目提供必要的信息 水平。项目1和项目2将研究癌细胞中IFNβ和TGFβ之间的拮抗相互作用 分化。在这些研究中，我们将确定是否可以使用刺激诱导的IFNβ来 消除LRIG1+细胞以改善对抗癌疗法的反应。我们将利用动物 模型，免疫型和分析核心B，以标准化我们的体内分析，包括临床前 评估癌症治疗和肿瘤微环境（TME）的表征。统计 分析将由计划生物统计学家Bo Hu博士和计划生物信息学家Fulai Jin博士进行 （核心B）。